The present disclosure relates generally to systems and methods for delivering electric fields to tissue and, in particular, to systems and methods for controlling and regenerating skin.
Wound care costs the U.S. healthcare system more than $20 billion each year. Among others, fire and burn injuries represent 1% of total injuries at a cost of $7.5 billion for total treatment and rehabilitation each year. In 2010 United States, a fire injury occurred every 30 minutes leading to 3,120 deaths and 17,720 injuries. Despite efforts, scars remain a major clinical and economic problem in the rehabilitation of burned and other injured patients, leading to physical, aesthetic, functional, psychological, and social stresses. Various approaches have been attempted over the years to treat scars, such as surgical excision, intra-lesional steroid and interferon injection, cryotherapy, laser therapy, irradiation, mechanical compression dressing, silicone sheet applications, to name a few. However, most treatments for keloidal and hypertrophic scars have offered minimal likelihood of improvement, with a recent meta review showing no statistically significant difference among the treatment options.
Wound healing is a dynamic, chronic process that is often divided into 4 overlapping phases: hemostasis, inflammation, proliferation, and remodeling. During hemostasis, constriction of the damaged vessels and clot formation physically limit blood loss. In the inflammatory phase, leukocytes and then monocytes accumulate to combat infection in the wounded tissue. In this phase, multiple cytokines and growth factors are released to the wound area and contribute to the fibroblast migration, differentiation and activity. During the proliferative phase, fibroblasts deposit new extracellular matrix and collagen and differentiate into myo-fibroblasts. In the final remodeling phase, re-organization of the closed wound environment occurs until repair is completed. Fetal wounds typically heal rapidly, without formation of a scab and with reduced inflammatory and angiogenic responses, exhibiting major differences compared to adult wound profiles of extracellular matrix and signaling. Moreover, in adults, the formation of hypertrophic scars (HTS) depends on the depth of injury and individual response, while in children, HTS are formed even in superficial wounds, burns and donor areas.
This complex dynamic process may be described using the concept of wound healing trajectory (FIG. 1A), which illustrates time-dependent cumulative effects of these multiple processes that occur from injury though healing. According to the healing trajectory curve, normally-healed tissues are characterized by complete restoration of function and structure. Chronic wounds, however, are characterized by incomplete restoration of structure and function. In proliferative scarring the healing process does not stop as it should and the tissue fails to reach a normal cell density and a balance between collagen deposition and degradation. Additionally, such processes may be further complicated by intrusion of infective biological pathogens or agents, interfering with repair processes and making clinical treatment more difficult.
Several systemic and genomic studies have identified potential cellular and extracellular factors that mediate the formation of proliferative scar. Current data show that alterations in coagulation, inflammation, angiogenesis, fibroplasia, contraction, remodeling, and mechanical tension correlate with the formation of HTS. However, the exact mechanisms associated with hypertrophic scarring have not yet been identified, leading to treatment procedures that have had limited clinical success. Thus, many conventional HSTs therapies do not take into account these complex interactions associated with would healing, and usually focus on a single target. For example, research on transforming growth factor ß (TGF-ß) revealed that TGF-ß1 and TGF-ß2 appear to be implicated in cutaneous scarring, while TGF-ß3 reduces scarring. However, a TGF-based therapy proposed thereafter failed in Phase III trials.
Humoral mediators appear to play an important role in proliferative scarring by altering fibroblast metabolism. It has been shown that signaling, which affects fibroblast metabolism, is different for individuals who suffer from proliferative scarring compared to those who do not. The major role of fibroblasts in wound healing is to replace the fibrin-based provisional matrix established during the inflammatory phase of wound healing with collagen-rich granulation tissue. The behavior of fibroblasts in the wound is highly dynamic (FIG. 1B) and varies at each healing phase. Fibroblasts reach the wound during the second or third day after the injury. Four days after the injury, fibroblasts are usually the major cell type in the developing granulation tissue. The wound fibroblast number increases initially through migration from nearby non-injured tissue and then through cell proliferation. Fibroblast density in the wound reaches its maximum between 7 and 14 days after injury. When the anatomic function of the tissue is mostly restored, the maturing granulation tissue undergoes remodeling leading to reduction of fibroblast density by apoptosis. Interestingly, clinical observations showed that in patients with proliferative scarring the apoptosis inhibitor—bcl-2 proto-oncogene is elevated while the apoptosis effector-interleukin-converting enzyme is decreased. These findings suggested that the apoptosis mechanisms are altered in patients with proliferative scarring.
Clinical control of cell density has been usually achieved by chemical factors, which affect the cell cycle, preventing or inducing proliferation. Such agents, however, cannot be precisely targeted and affect multiple cell types. For example, Tamoxifen, a synthetic non-steroidal anti-estrogen, has been shown to have multiple side effects. Those side effects include altered RNA transcription, decreased cellular proliferation, delay or arrest of the cells in the G1 phase of the cell cycle, and interference with multiple growth factors such as TGF-b and insulin-like growth factor.
In addition to efforts for improving wound care, the desire for a rejuvenated appearance has led to over 2.1 million skin rejuvenation procedures and accounted for 1.8 billion in spending in the US alone (2012) in the treatment of scars, striae, age-related rhytids, photodamage, acne, and trauma. In fact, minimally invasive aesthetic body shaping is the fastest growing sector of the rapidly expanding aesthetic market. From 1997 to 2012, there was a 500 percent increase in the total number of minimally-invasive procedures including skin resurfacing and laser procedures. This growth is driven by an aging population and increased social acceptance of aesthetic procedures, as well as significant emotional and psychological sequelae as result in physical alterations.
Overall, skin rejuvenation methods aim to remove damaged tissue and stimulate new growth of healthy collagen, skin cells, and elastin fibers. Currently the most popular therapies include percutaneous collagen induction (PCI) and laser therapies. PCI has a low side effect profile, but has very limited clinical data. Although laser treatments have good clinical data, they also have a poor side effect profile with many patients experiencing prolonged erythema, scaring, and dyspigmentation. The market needs a technology with fewer side effects, a better safety profile, lower cost, and one that is convenient enough to be sold over the counter.
Experimental data has shown that pulsed electric fields applied to cells may trigger multiple biochemical mechanisms, shown in FIG. 2, such as stimulating electric fields (SEF), reversible electroporation (RE), non-thermal irreversible electroporation (IRE), and thermal damages. These are known to affect cell and tissue metabolism by regenerative stimulation at the lower amplitudes, and, in addition, permeabilization at the higher ones. In the case of electroporation, the pulsed electric fields cause changes in cell membrane permeability, which may be reversible when the change in permeabilization is temporary, and cells survive. Applications of RE have involved gene delivery to cells and tissues, and cell fusion. In addition, RE has also been the basis for a new cancer treatment therapy, known as “electrochemotherapy,” whereby cancer cell-specific cytotoxic drugs are introduced into cells through temporary membrane openings created by the pulsed electric fields.
Therefore, given the above, there is a need for systems and methods for controlling tissue and tissue regenerating processes using applied pulsed electric fields.